Novel stable palmitamide ethanol crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of hexadecanamide ethanol crystal form compounds, and particularly relates to a novel stable hexadecanamide ethanol crystal form and a preparation method thereof. The preparation method comprises the following steps: S1, preparing an ethanolamine solution, S2, mixing a palmitoyl chloride solution and ethanolamine for reaction, and filtering to obtain a palmitamide ethanol crude product; s3, adding the palmitamide ethanol crude product into a methanol or ethanol solution for recrystallization; and S4, drying to obtain a palmitamide ethanol crystal. Compared with the prior art, the novel crystal form of hexadecanamide ethanol provided by the invention has the advantages that the production cost is obviously reduced, and the purity is higher.

Description

Technical Field

[0001] This invention relates to the field of hexadecamide ethanol crystal form compound technology, and particularly to a stable new crystal form of hexadecamide ethanol and its preparation method. Background Technology

[0002] Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide, structure shown below) was first discovered in egg yolks, soybeans, and peanut oil in 1957, and subsequently in mammalian tissues in 1965. It is one of the most common N-acylethanolamines (NAEs). The initial identification of PEA, along with the demonstration in the same study of its effectiveness in a localized passive joint anaphylaxis assay in guinea pigs, was based on early research suggesting that components of egg yolks might be beneficial for rheumatoid arthritis. Subsequent clinical studies have shown that PEA may play a useful role in treating a range of conditions, from pain to eczema.

[0003]

[0004] In the prior art, common methods for synthesizing hexadecamide ethanol include:

[0005] (1) Hexadecylamine ethanol is synthesized by reacting ethanolamine with palmitic acid under the catalysis of a catalyst, but the catalyst cost is high and the purity of the final product is only 95% to 98%.

[0006] (2) Hexadecylamide ethanol is synthesized under the catalysis of aldolase. This method produces a purer product and is more human-friendly. However, the high cost of aldolase makes this method unsuitable for large-scale industrial production. Summary of the Invention

[0007] The purpose of this invention is to provide a stable new crystal form of hexadecamide ethanol, which significantly reduces production costs compared to existing processes, while also exhibiting good crystal form stability.

[0008] The above-mentioned technical objective of the present invention is achieved through the following technical solution: a stable new crystal form of hexadecylamide ethanol, wherein the XRD diffraction pattern of the new crystal form has characteristic peaks at 2θ of 8.1±0.2°, 12.2±0.2°, 18.4±0.2°, 20.46±0.2°, 22.54±0.2°, 28.8±0.2°, 32.84±0.2°, 33.0±0.2°, 39.2±0.2°, 39.4±0.2°, 43.6±0.2°, and 43.8±0.2°.

[0009] It is well known in the field of crystallography that, for any given crystal form, the angular peak position may vary slightly due to factors such as sample preparation conditions, sample displacement, and the presence of an internal standard. In this invention, the variability of the angular peak position is ±0.2° in 2θ. Furthermore, the relative peak intensity of a given crystal form may vary due to differences in crystallite size and non-random crystallite orientation during sample preparation for XRD analysis. It is well known in the art that this variability can account for the above factors without hindering the definitive identification of the crystal form.

[0010] In some specific embodiments, the X-ray powder diffraction (XRD) is obtained from a copper radiation source operating at 40V / 15mA with a scan rate of 10° / min. The resulting powder diffraction characteristics are shown in the table below:

[0011]

[0012] In a second aspect, the present invention provides a method for preparing the above-mentioned stable hexadecylamide ethanol novel crystal form, comprising the following steps:

[0013] S1: Preparation of ethanolamine solution:

[0014] Add ethanolamine to water and stir until homogeneous to obtain an aqueous solution of ethanolamine;

[0015] S2: Condensation reaction:

[0016] At room temperature, palmitoyl chloride is added dropwise to an aqueous solution of ethanolamine at a molar ratio of 1:1.5~2.5. The mixture is stirred and reacted, and then filtered to obtain crude hexadecylamide ethanol. The mother liquor obtained after filtration can be recycled and used as water for the preparation of the aqueous solution of ethanolamine in step S1.

[0017] S3: Recrystallization

[0018] Crude hexadecyl ethanol was added to methanol or ethanol and recrystallized to obtain wet hexadecyl ethanol crystals.

[0019] S4: Drying:

[0020] The wet hexadecamide ethanol crystals were placed in a vacuum drying oven, the temperature was maintained at 30~50℃, the pressure was reduced to a vacuum degree of -0.05MPa or higher, and dried to constant weight to obtain hexadecamide ethanol crystals.

[0021] Preferably, the ratio of ethanolamine to water in step S1 is 1g:4~20ml.

[0022] Preferably, the molar ratio of palmitoyl chloride to ethanolamine in step S2 is 1:1.5~2.5.

[0023] Preferably, the mother liquor filtered in step S2 can be directly used as water in step S1.

[0024] Preferably, in step S3, the ratio of crude hexadecylamide ethanol to methanol or ethanol is 1g:3~10mL.

[0025] In summary, the present invention has the following beneficial effects: By adopting a green aqueous phase recycling method, the aqueous phase used in the production process can be recycled. Compared with the prior art, it avoids the use of expensive aldolase or large amounts of chemical solvents, reduces waste residue, has low production costs, is more environmentally friendly, and the resulting product has higher crystal purity. Moreover, the process is simple, reproducible, and easy to realize industrial production. Attached Figure Description

[0026] Figure 1 The X-ray powder diffraction pattern of the hexadecylamide ethanol crystal form described in Example 1;

[0027] Figure 2 This is a liquid chromatography purity test report for the hexadecanoic acid ethanol crystal form described in Example 1;

[0028] Figure 3 The X-ray powder diffraction pattern of the hexadecylamide ethanol crystal form described in Example 2;

[0029] Figure 4 This is a liquid chromatography purity test report for the hexadecamide ethanol crystal form described in Example 2;

[0030] Figure 5 The X-ray powder diffraction pattern of the hexadecylamide ethanol crystal form described in Example 3;

[0031] Figure 6 This is a liquid chromatography purity test report for the hexadecamide ethanol crystal form described in Example 3;

[0032] Figure 7 The X-ray powder diffraction pattern of the hexadecylamide ethanol crystal form described in Example 4;

[0033] Figure 8 This is a liquid chromatography purity test report for the hexadecamide ethanol crystal form described in Example 4. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the accompanying drawings.

[0035] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

[0036] Example 1:

[0037] In this embodiment, a hexadecylamide ethanol crystal form is provided, and the preparation method of the crystal form is as follows:

[0038] At room temperature, 9.15 g (0.15 mol) of ethanolamine was added to 36.6 ml of water and stirred until homogeneous. Then, 27.4 g (0.1 mol) of palmitoyl chloride was added dropwise to the aqueous solution of ethanolamine, and a solid gradually precipitated out. After the addition was complete, the mixture was stirred for 30 min and then filtered to obtain crude hexadecylamide ethanol with a wet weight of 35.4 g.

[0039] Crude hexadecamide ethanol was added to 106.2 ml of methanol, heated to 50°C, stirred until gradually dissolved, and then cooled to room temperature for 0.5 h before filtration to obtain wet hexadecamide ethanol crystals.

[0040] The wet hexadecamide ethanol crystals were placed in a vacuum drying oven, the temperature was set at 45℃, and dried to constant weight under a vacuum of -0.07 MPa to obtain 27.8 g of hexadecamide ethanol crystals with a liquid phase purity of 99.72%.

[0041] Example 2:

[0042] In this embodiment, a hexadecylamide ethanol crystal form is provided, and the preparation method of the crystal form is as follows:

[0043] At room temperature, 15.26 g (0.25 mol) of ethanolamine was added to 305.2 ml of water and stirred until homogeneous. Then, 27.4 g (0.1 mol) of palmitoyl chloride was added dropwise to the aqueous solution of ethanolamine, and a solid gradually precipitated out. After the addition was complete, the mixture was stirred for 30 min and then filtered to obtain crude hexadecylamide ethanol with a wet weight of 35.1 g.

[0044] Crude hexadecamide ethanol was added to 210.6 ml of methanol, heated to 50°C, stirred until gradually dissolved, and then cooled to room temperature for 0.5 h before filtration to obtain wet hexadecamide ethanol crystals.

[0045] The wet hexadecamide ethanol crystals were placed in a vacuum drying oven, the temperature was set at 45℃, and dried to constant weight under a vacuum of -0.07 MPa to obtain 27.1 g of hexadecamide ethanol crystals with a liquid phase purity of 99.76%.

[0046] Example 3

[0047] In this embodiment, a hexadecylamide ethanol crystal form is provided, and the preparation method of the crystal form is as follows:

[0048] At room temperature, 12.2 g (0.2 mol) of ethanolamine was added to 122 ml of water and stirred until homogeneous. Then, 27.4 g (0.1 mol) of palmitoyl chloride was added dropwise to the ethanolamine aqueous solution, and a solid gradually precipitated out. After the addition was complete, the mixture was stirred for 30 min, and then filtered to obtain crude hexadecylamide ethanol with a wet weight of 34.8 g. The mother liquor obtained from filtration was collected.

[0049] Crude hexadecamide ethanol was added to 348 ml of ethanol, heated to 50°C, stirred until gradually dissolved, and then cooled to room temperature for 0.5 h before filtration to obtain wet hexadecamide ethanol crystals.

[0050] The wet hexadecamide ethanol crystals were placed in a vacuum drying oven, the temperature was set at 45℃, and dried to constant weight under a vacuum of -0.07 MPa to obtain 25.5 g of hexadecamide ethanol crystals with a liquid phase purity of 99.80%.

[0051] Example 4:

[0052] In this embodiment, a hexadecylamide ethanol crystal form is provided, and the preparation method of the crystal form is as follows:

[0053] At room temperature, 9.15 g (0.15 mol) of ethanolamine was added to 45 ml of the mother liquor water from step ① of Example 3 and stirred until homogeneous. Then, 27.4 g (0.1 mol) of palmitoyl chloride was added dropwise to the aqueous solution of ethanolamine, and a solid gradually precipitated out. After the addition was complete, the mixture was stirred for 30 min and then filtered to obtain crude hexadecylamide ethanol with a wet weight of 35.4 g.

[0054] Crude hexadecamide ethanol was added to 170 ml of ethanol, heated to 50 °C, stirred and gradually dissolved, then cooled to room temperature for 0.5 h, and filtered to obtain wet hexadecamide ethanol crystals.

[0055] The wet hexadecamide ethanol crystals were placed in a vacuum drying oven, the temperature was set at 45℃, and dried to constant weight under a vacuum of -0.07 MPa to obtain 26.4 g of hexadecamide ethanol crystals with a liquid phase purity of 99.75%.

Claims

1. A stable new crystalline form of hexadecylamide ethanol, characterized in that, The XRD diffraction pattern of the new crystal form has characteristic peaks at 2θ of 8.1±0.2°, 12.2±0.2°, 18.4±0.2°, 22.54±0.2°, 39.2±0.2°, and 43.6±0.2°.

2. The novel hexadecanoic acid ethanol crystal form according to claim 1, characterized in that, The XRD diffraction pattern of the new crystal form has characteristic peaks at any one or more of the following locations at 2θ: 20.46±0.2°, 28.8±0.2°, 32.84±0.2°, 33.0±0.2°, 39.2±0.2°, 43.8±0.2°.

3. The novel hexadecanoic acid ethanol crystal form according to claim 1 or 2, characterized in that, The XRD diffraction scanning range is 5-90°, and the scanning rate is 10° / min.

4. A method for preparing a novel crystal form of hexadecylamide ethanol, characterized in that, Includes the following steps: S1: Preparation of ethanolamine aqueous solution: Add ethanolamine to water and stir until homogeneous; S2: Condensation reaction: Palmitoyl chloride is added to an aqueous solution of ethanolamine, the mixture is stirred and reacted, and then filtered to obtain crude hexadecylamide ethanol. S3: Recrystallization: The above crude hexadecylamide ethanol is added to methanol or ethanol and recrystallized to obtain wet hexadecylamide ethanol crystals; S4: Drying: The above wet hexadecamide ethanol crystal material is placed in a vacuum drying oven and dried to obtain hexadecamide ethanol crystals.

5. The method for preparing the new hexadecylamide ethanol crystal form according to claim 4, characterized in that, The ratio of ethanolamine to water in S1 is 1g:4~20ml.

6. The method for preparing the new hexadecanoic acid ethanol crystal form according to claim 4, characterized in that, In S2, the molar ratio of palmitoyl chloride to ethanolamine is 1:1.5~2.

5.

7. The method for preparing the new hexadecylamide ethanol crystal form according to claim 4, characterized in that, The ratio of crude hexadecylamide ethanol to methanol or ethanol in S3 is 1g:3~10mL.

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